Copper-catalyzed N-alkoxyalkylation of nucleobases involving direct functionalization of sp3 CeH bonds adjacent to oxygen atoms

Article abstract of DOI:10.1016/j.tet.2012.11.020

N-Alkoxyalkylation of nucleobases was realized by the copper-catalyzed peroxide-promoted coupling of nucleobases with readily available saturated ethers. Both purines and pyrimidines could be N-alkoxyalkylated through this method in moderate to good yields. 2D-NMR revealed that N9-alkoxyalkylation preferentially occurred when purines were used in this reaction. Crown Copyright

Full text of DOI:10.1016/j.tet.2012.11.020

Tetrahedron 69 (2013) 577e582
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed N-alkoxyalkylation of nucleobases involving direct
functionalization of sp3 CeH bonds adjacent to oxygen atoms
*
*
Rui Huang, Chunsong Xie , Lin Huang, Jinhua Liu
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2012
Received in revised form 31 October 2012
Accepted 6 November 2012
Available online 10 November 2012
N-Alkoxyalkylation of nucleobases was realized by the copper-catalyzed peroxide-promoted coupling of
nucleobases with readily available saturated ethers. Both purines and pyrimidines could be N-alkox-
yalkylated through this method in moderate to good yields. 2D-NMR revealed that N9-alkoxyalkylation
preferentially occurred when purines were used in this reaction.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
N-Alkoxyalkylated nucleobase
Copper catalysis
CeH functionalization
1. Introduction
alkoxyalkylation of nucleobases could be realized via the coinage-
metals catalyzed direct coupling of saturated ethers and nucleo-
The N-alkoxyalkylation of nucleobases has received much at-
tention mainly because that N-alkoxyalkylated nucleobases are
core structures in many biologically active analogues of natural
nucleosides.1 Traditionally, this could be realized by the N-alkox-
yalkylation of natural and modified nucleobases taking advantage
of ɑ-halogenated ethers,2 ɑ-acetoxyl ethers,3 and alkyl vinyl ethers4
as alkylating reagents. Although had proven to be efficient, these
alkylating partners often needed multistep pre-synthesis, and
strong bases, stoichiometric Lewis acids or Bronsted acids were
always required in these processes. Recently, Guo et al. had re-
ported a novel method, which directly utilized alkyl ethers to al-
kylate purines under thermal and irradiation conditions.5 However,
this method still suffered from that the nucleobases were limited to
purines, and also that the need of stoichiometric (diacetoxyiodo)
benzene as reaction promoter, which would generate iodobenzene
byproduct during the reaction. So the development of novel and
direct access to N-alkoxyalkylated nucleobases, especially from
readily available materials and under mild conditions, is still of
much significance.
bases. In this paper, we will report our findings concerning on this
new strategy.
2. Results and discussion
We started our investigation by choosing 2,6-dichloropurine 1a
and THF (tetrahydrofuran) 2a as model substrates. The subjection
of 1a to react with 2a in the presence of 10 mol % CuCl2 and 5 equiv
TBHP (tert-butyl hydroperoxide) at 70 ꢀC for 24 h gave a 38% yield of
aimed product 3aa (Table 1, entry 1). 2D-NMR experiments in-
dicated that the alkoxyalkylation happened regioselectively,
affording the N9-alkoxyalkylated 2,6-dichloropurine as the major
product (see SD for details).
The addition of bidentate nitrogen ligands proved to be advanta-
geous. A higher yield (65%)was obtained when using 2,20-bipyridyl as
the ligand (Table 1, entry 2). Other bidentate nitrogen ligands, such as
1,10-phenanthroline,
N1,N1,N2,N2-tetramethylethane-1,2-diamine,
N1,N2-dimethylethane-1,2-diamine, and ethane-1,2-diamine all gave
worse results (Table 1, entries 3e6). CuCl2 had proven to be the best
catalyst, and lower yields were given when using other copper
complexes, such as CuBr2, Cu(OAc)2, CuCl, CuBr, and CuI (Table 1,
entries 7e11). Increasing of the reaction concentration proved to be
beneficial, and a 74% yield of 3aa was provided when conducting the
reaction in2 mLTHF(Table 1, entry12). However, furtherreducing the
volume of the solvent was found to be detrimental with lower yields
were produced (Table 1, entries 13e15). TBHP had proven to be the
most efficientoxidant, and the reactionwas totally halted when using
During the past few years, transition metal catalyzed direct
functionalization of sp3 CeH bonds adjacent to heteroatoms had
been much studied.6 Among these, iron and copper-catalyzed di-
rect a-CeH activation of saturated ethers had been well in-
vestigated.7 Based on these progresses, we envisioned that the N-
* Corresponding authors. Tel.: þ86 571 28866142; fax: þ86 571 28865630;
e-mail addresses: chunsongxie@hznu.edu.cn (C. Xie), ljh@hznu.edu.cn (J. Liu).
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.020

578
R. Huang et al. / Tetrahedron 69 (2013) 577e582
Table 1 (continued)
Table 1
The optimization Worka
Entry Catalyst
Ligand
Oxidant
TBHP
T
ꢀ C t (h) V2a (mL) Yield %b
Cl
Cl
N
N
N
25
26
CuCl2
CuCl2
CuCl2
70
70
70
3
48
24
2
2
2
29
74
73
N
N
O
conditions
N
N
N
N
N
N
N
Cl
O
N
H
Cl
N
TBHP
TBHP
1a
2a
3aa
T
ꢀ C t (h) V2a (mL) Yield %b
27c
Entry Catalyst
Ligand
Oxidant
1
CuCl2
No
TBHP
70
24
6
38
a
Reaction conditions: 1a (1 mmol), catalyst (0.1 mmol), ligand (0.1 mmol), oxi-
dant (5 mmol).
2
CuCl2
TBHP
70
24
6
65
b
c
N
N
Isolated yield.
20 mol % CuCl2 and bipyridyl were used.
3
4
CuCl2
CuCl2
TBHP
TBHP
70
70
24
24
6
6
47
35
N
N
N
N
2-(tert-butylperoxy)-2-methylpropaneorO2 asthepromoter(Table 1,
entries 16e20). Moreover, it was found that 70 ꢀC was necessary for
thereaction, since lowering the reaction temperature delivered lower
yields (Table 1, entries 21 and 22). Furthermore, 24 h had proven to be
necessary reaction time, and the yields gradually fell down when
shortening the reaction time (Table 1, entries 23e25). However, fur-
therelongation of the reaction time seemed to be of no use either, and
acomparableyieldwasafforded whenthereactionwasconductedfor
48h(Table 1, entry26). Asimilarresultwasalsoobtainedinthecaseof
increasing the loading of the reaction catalyst. When performing the
reaction under the circumstance that the catalyst loading was 20%,
a comparable yield (73%) was afforded (Table 1, entry 27).
With the optimal condition in hand, we next studied the scope
of the reaction and the results were summarized in Table 2. Various
substituted purines 1bee were subjected to the reaction and gave
the expected nucleoside analogues 3baeea in moderate yields
(Table 2, entries 2e5). A variety of groups, such as Cl and Boc were
well tolerated, allowing the further conversion of these nucleoside
analogues. Inspired by the elegant findings on the ligand-promoted
copper-catalyzed aerobic CeH functionalization reported by Stahl
and co-workers,8 we found that in the course of our experiment
using 1e as the nucleobase, switching the ligand to more electron-
poor bidentate nitrogen ligand 1,10-phenanthroline-5,6-dione L2
was somewhat beneficial with a slightly higher yield (55%) being
delivered. Similar results were also obtained in the case of pyrim-
idine derivatives 1f and 1g (Table 2, entries 6 and 7). When using
Boc protected thymine 1f as the substrate, a moderate yield (50%)
was produced under the standard condition. After increasing the
catalyst loading to 20%, just a slightly higher yield (54%) was pro-
vided. When changing the ligand to L2, a 58% yield could be ob-
tained even though the catalyst loading was 10%. Analogously, in
the case of cytosine derivative 1g, a slightly higher yield (40%) was
produced when using L2 than L1. Although the exact reason for this
ligand effect remained unclear at present, we inferred that the
lowering of the electron density on ligand nitrogens would lead to
an increase of the oxidation capacity of the catalytically active
metal center toward the peroxides.
5
6
7
CuCl2
CuCl2
CuBr2
TBHP
TBHP
TBHP
70
70
70
24
24
24
6
6
6
35
41
43
NH HN
H2N NH2
N
N
8
Cu(OAc)2
CuCl
TBHP
70
70
70
70
70
70
70
70
70
70
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
6
59
40
38
45
74
39
26
20
NR
50
53
20
NR
50
30
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
9
TBHP
6
10
11
12
13
14
15
16
17
18
19
20
21
22
CuBr
TBHP
6
CuI
TBHP
6
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
TBHP
TBHP
2
1
TBHP
0.5
0.1
2
TBHP
(t-BuO)2
(PhCO2)2
2
PhCO3t-Bu 70
2
H2O2
O2
70
70
50
RT
2
In addition, we also examined the reaction of free natural
nucleobases, such as cytosine 1h with 2a. Just a trace amount of
desired product 3ha could be detected. Instead, the 4-amino
2
alkoxyalkylated product 3ha0 was produced in
a 45% yield
(Scheme 1). Still, this transformation is of significance due to that
the N4-alkoxyalkyalted pyrimidines have been found to have in-
teresting biological activities.9
After surveying various nucleobases, we turned our attention to
test various ethers. Pleasingly, various saturated ethers had proven
to be reliable reactants as illustrated in Table 3. When using 1-
butoxybutane 2b, tetrahydro-2H-pyran 2c, and dioxane 2d to re-
act with 2,6-dichloropurine 1a, a variety of N-alkoxyalkylated
products 3abead were produced in moderate yields (Table 3,
TBHP
TBHP
2
2
23
24
CuCl2
CuCl2
TBHP
TBHP
70
70
12
6
2
2
52
38
N
N
N
N

R. Huang et al. / Tetrahedron 69 (2013) 577e582
579
Table 2
Table 3
The coupling of THF with Nucleobasesa
The N-alkoxyalkylation of 2,6-dichloropurinea
Cl
N
N
N
N
L
N
N
Cl
R
CuCl 10 mol%
N
N
N
N
O
N
O
R
N
N
L
or L 10 mol%
O
R
CuCl2 10 mol%
L1 or L2 10 mol%
O
L1
:
:
N
N
H
N
R
+
Cl
N
O
N
O
O
R1
N
H
TBHP 5 equiv
70 C, 24 h
H
H
Cl
N
or
+
or
O
R
3
L
:
TBHP 5 equiv
70 oC, 24 h
O
O
1a
2
2a
N
N
L2
NH
NH
R
R
N
N
N
O
N
H
O
O
Entry
1
Ether
Product
Yield %b
1
3
Cl
N
H
N
Yield %b
O
Entry
1
Nucleobase
Product
35
N
43c
52d
N
Cl
2b
O
Cl
N
N
3ab
Cl
N
N
N
N
74
Cl
N
Cl
N
H
O
Cl
N
N
N
N
1a
3aa
2
58
Cl
O
H
2c
O
Cl
Cl
N
3ac
N
N
N
N
N
2
3
65
51
Cl
N
N
N
H
O
1b
N
N
O
O
N
N
3ba
3
4
35
Cl
Cl
O
O
H
Boc
Boc
N
2d
43c
51d
N
Boc
N
Boc
N
3ad
3ae
N
N
Cl
N
N
N
N
H
O
N
N
N
1c
3ca
O
76
O
H
2e
Cl
N
Cl
N
N
N
N
N
N
4
55
Boc
Boc
N
H
N
Boc
Cl
N
Boc
O
N
1d
N
O
3da
H
5
70e
N
N
Cl
2f
O
Cl
N
Cl
3af
N
N
a
5
6
50
Reaction conditions: 1a (1 mmol), 2 (2 mL), CuCl2 (0.1 mmol), L1 (0.1 mmol),
N
55d
O
N
N
TBHP (5 mmol).
H
1e
b
3ea
3fa
Isolated yields.
20 mol % CuCl2 and bipyridyl were used.
2 instead of L1 was used.
The diastereoselectivity was nearly 1:1.
c
O
O
d
Boc
O
L
N
Boc
O
e
N
50
N
54c
58d
N
H
O
1f
entries 1e3). Once again, for the substrates that led to low yields
(2b and 2d), we tested the reaction with 20% catalyst loading or
changing the ligand to L2, and found that the yields increased
gradually. When using the unsymmetrical ether like isochroman 2e
as the alkylating component, a good yield (76%) of regioselective
CeH functionalization product 3ae was produced with the CeN
bond forming at the more acidic methylene position (Table 3, entry
4). Interestingly, unsymmetrical dialkyl ether, such as tetrahydro-2-
methylfuran 2f was also proven to be a reliable reaction partner
with 1a, producing the regioselective nucleosidation product 3af in
a 70% yield and 1:1 diastereoselectivity (Table 3, entry 5). This is of
much significance due to that this kind of 50-substituted products
represent structurally ubiquitous scaffolds in many useful nucleo-
side analogues.10
Besides these, we also conducted the reaction between 2,6-
dichloropurin 1a and diethoxymethane 2g, and surprisingly found
that a N-ethoxymethylated nucleobase 3ag was produced in a 35%
yield (Scheme 2). After changing the reaction ligand to L2, a higher
yield (55%) was obtained. Although did not get our anticipated
product, we still believed that this reaction was noteworthy, since it
offered a good pathway for the synthesis of nucleoside analogues
bearing an unsymmetrical dialkyl ether moiety.11 Moreover, the fact
Boc
O
Boc
N
Boc
Boc
N
N
N
7
35
40d
N
O
N
H
O
1g
3ga
a
Reaction conditions: 1 (1 mmol), 2a (2 mL), CuCl2 (0.1 mmol), L1 (0.1 mmol),
TBHP (5 mmol).
b
Isolated yields.
20 mol % CuCl2 and bipyridyl were used.
L2 instead of L1 was used.
c
d
H
NH2
N
N
O
NH2
N
CuCl2 10 mol%
2,2'-bipyridyl 10 mol%
O
N
H
+
+
TBHP 5 equiv
70 oC, 24 h
N
O
NH
N
H
O
O
O
1h
2a
3ha, trace
3ha', 45%
Scheme 1. The N-alkoxyalkylation of free cytosine.

580
R. Huang et al. / Tetrahedron 69 (2013) 577e582
Cl
N
N
N
Cl
CuCl2 10 mol%
L1 or L2 10 mol%
L1
:
:
35%
55%
N
N
N
H
Cl
N
N
O
N
O
1a
N
Cl
+
TBHP 5 equiv
DMSO (c = 0.5 M)
70 oC, 48 h
O
O
O
L2
3ag
H
2g
N
N
Scheme 2. The N-ethoxymethylation of 1a.
that this reaction could proceed in DMSO indicated that the use of
ether as reaction solvent was not a necessity in the reaction.12
Based on these results, a plausible mechanism was proposed
as depicted in Scheme 4. As an initial of the cascade events, the
single electron transfer (SET) of Cu(II) complex with TBHP gen-
erated active Cu(I) species. Then the SET between Cu(I) and TBHP
produced the tert-butoxyl radical II and regenerated the Cu(II)
species.15 Subsequently, hydrogen atom abstraction of ethers 2 by
II would happen, generating the alkyl radical III.16 Next, nucle-
obases 1 would be converted into radical specie IV by reacting
with II or III. Finally, the coupling of III and IV would take place,
3. Mechanistic consideration
The exact reaction pathway of this reaction seems to be compli-
cated andstill remains unclearat this moment. To gain some clues for
the reaction mechanism, we conducted the radical inhibition ex-
periment by employing TEMPO (2,2,6,6-tetramethylpiperidine-1-
oxyl) as the radical scavenger, and found that the reaction was par-
tially suppressed affording the N-alkoxyalkyl 2,6-dichloropurine 3aa
in a 8% yield (Scheme 3a). This implied that the carbon radical might
giving the N-alkoxyalkylated nucleobases
3 as the reaction
product.5
Cl
Cl
CuCl2, 10 mol%
2,2'-bipyridyl 10 mol%
N
N
N
N
O
N
N
a)
b)
N
Cl
O
TBHP 5 equiv
TEMPO 6 equiv
70 oC, 24 h
N
H
Cl
Cl
N
1a
3aa, 8%
2a
Cl
N
CuCl2, 10 mol%
2,2'-bipyridyl 10 mol%
N
complex mixture
O
TBHP 5 equiv
70 oC, 24 h
N
H
1a
2h
Scheme 3. The mechanism experiment.
be involved in the reaction, and a completelycopper-mediated inner-
sphere mechanism seemed to be unlikely for this reaction. In addi-
tion, we had also performed a radical clock experiment by using
((cyclopropylmethoxy)methyl)cyclopropane 2h as the substrate, but
got a quite complex reaction system, which was unable to give any-
thing valuable for the reaction mechanism (Scheme 3b).
LnCu(II)
t-BuO2H
t-BuO2H
+
t-BuO2
+
+
+
H+
1)
2)
LnCu(I)
LnCu(II)
I
H+
LnCu(I)
+
t-BuO
II
+
H2O
R2
O
R2
O
However, there were still some results should be noted in the
experiment. First, the N9-alkoxyalkylated 2,6-dichloropurine 3aa
was site selectively formed. This was quite different with the
classic glycosidation that was believed to proceed through ionic
mechanisms, since most of them produced both N7 and N9-
alkoxyalkylated products.13 In contrary, this selectivity was quite
consistent with the reported DIB/I2 promoted N-alkylation of
purines, which was assumed to operate through an in-
termolecular hydrogen abstraction procedure.5 Second, the
unactivated pyrimidines 1f and 1g were proven to be competent
substrates in the reaction, delivering the regioselectively N-
alkoxyalkylated products without any O-alkoxyalkylation hap-
pened. Due to the low nucleophilicity and low acidity of these
cyclic amide substrates, the direct nucleophilic attack or the for-
mation of nucleophilic amido anions via deprotonation seemed
unlikely.14
R1
+
R1
3)
+
t-BuO
t-BuOH
2
II
III
or
t-BuO
III
4)
5)
+
t-BuOH
B
IV
BH
1
B
O
R2
III + IV
R1
3
Scheme 4. Proposed mechanism.
4. Conclusion
In summary, we have disclosed a novel access to N-alkox-
yalkylated nucleobases by direct coupling of saturated ethers with

R. Huang et al. / Tetrahedron 69 (2013) 577e582
581
nucleobases. This copper-catalyzed sp3 CeH functionalization in-
volved transformation shows general tolerance to a variety of
functionalities, furnishing various purine, and pyrimidine nucleo-
side analogues in moderate to good yields. In the whole of this
reaction, no wasteful byproduct except H2O and t-BuOH is gener-
ated, making this method quite attractive for its economical and
environmental significance. Further application of this nucleoside
analogue synthesis in a variety of pharmaceuticals and biomedical
reagents is currently ongoing in our laboratory.
83.6, 70.0, 32.5, 27.9, 24.2. HRMS (EI) calcd for C19H26ClN5O5: [M]þ
439.1622; found, 439.1635.
5.2.5. 4-Chloro-7-(tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimi-
dine (3ea). Brownoil,55%yield.1HNMR(400MHz, CDCl3,TMS)
d8.64
(s, 1H), 7.37 (d, J¼4.4 Hz, 1H), 6.62 (d, J¼4.0 Hz, 1H), 6.53 (dd, J¼6.8,
3.6 Hz, 1H), 4.21e4.27 (m, 1H), 4.01e4.07 (m, 1H), 2.46e2.55 (m, 1H),
2.25e2.42 (m, 1H), 2.12e2.21 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
152.0,150.6,150.5,126.2,118.2, 99.9, 85.3, 69.3, 32.5, 24.7. HRMS (ESI)
calcd for C10H10ClN3O: [MþH]þ 224.0580; found, 224.0592.
5. Experimental
5.1. General
5.2.6. tert-Butyl 2,3-dihydro-3-(tetrahydrofuran-2-yl)-5-methyl-2,6-
dioxopyrimidine-1(6H)-carboxylate (3fa). White powder, 58% yield.
Mp 106e108 ꢀC. 1H NMR (400 MHz, CDCl3, TMS)
d 7.58 (m, 1H), 6.64
All the reactions were carried out under air atmosphere in oven-
dried flasks. THF was distilled from Na using benzophenone as
indicator. Protected nucleobases 1c, 1d, 1f, and 1g were synthesized
according to reference methods.17e19 1,10-Phenanthroline-5,6-
dione L2 was prepared by the reference method.20 Other mate-
rials were purchased from commercial sources, and used without
additional purification. 1H NMR spectra were recorded at 400 MHz
using TMS as internal standard. 13C NMR spectra were recorded at
100 MHz. Mass spectroscopy data were collected on a HRMS-ESI or
HRMS-EI instrument.
(dd, J¼8.0, 4.4 Hz, 1H), 4.33 (dd, J¼15.2, 6.8 Hz, 1H), 3.93 (m, 1H),
2.46 (m, 1H), 2.35 (m, 1H), 2.22 (m, 1H), 1.99 (m, 1H), 1.93 (d,
J¼1.2 Hz, 1H), 1.59 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 163.2, 148.6,
147.8, 133.5, 111.6, 86.5, 85.1, 70.6, 28.8, 27.8, 26.5, 13.2. HRMS (EI)
calcd for C14H20N2O5: [M]þ 296.1372; found, 296.1372.
5.2.7. 4-(Di(tert-butyloxycarbonyl)amino)-1-(tetrahydrofuran-2-yl)-
2-oxopyrimidine (3ga). Pale yellow powder, 40% yield. Mp
159e161 ꢀC. 1H NMR (400 MHz, CDCl3, TMS)
d
7.73 (d, J¼7.6 Hz, 1H),
7.03 (d, J¼7.6 Hz, 1H), 6.00 (dd, J¼6.0, 2.4 Hz, 1H), 4.23 (m, 1H), 4.03
(m, 1H), 2.47 (m, 1H), 2.14 (m, 1H), 2.02 (m, 1H), 1.79 (m, 1H), 1.56 (s,
5.2. General procedure of the alkylation reaction
18H); 13C NMR (100 MHz, CDCl3)
d 162.4, 154.4, 149.7, 142.6, 95.6,
88.9, 84.8, 70.5, 33.2, 27.7, 23.4. HRMS (ESI) calcd for C18H27N3O6:
Into an oven-dried flask, nucleobase (1.0 mmol), CuCl2
(0.1 mmol), ligand (0.1 mmol), and TBHP (5e6 M in decane,
5.0 mmol) were added in ether (2 mL) at room temperature. The
mixture was allowed to react at 70 ꢀC for 24 h. After the completion
of the reaction, the mixture was filtered through a pad of Celite, and
the filtrate was concentrated until the solvent was completely re-
moved. The residue was then separated on a silica gel column, and
gave the final product.
[MþH]þ 382.1973; found, 382.1980.
5.2.8. 4-(Tetrahydrofuran-2-ylamino)pyrimidin-2(1H)-one (3ha0).
White powder, 45% yield. Mp 175e177 ꢀC. 1H NMR (400 MHz,
CDCl3, TMS)
(d, J¼6.8 Hz, 1H), 4.21 (m, 1H), 3.99 (m, 1H), 2.43 (m, 1H), 2.12 (m,
1H), 2.01 (m, 1H), 1.83 (m, 1H); 13C NMR (100 MHz, CD3OD)
165.3,
d
7.47 (d, J¼8.0 Hz,1H), 6.02 (dd, J¼6.4, 3.6 Hz,1H), 5.70
d
141.9, 94.8, 90.3, 80.9, 66.8, 30.8, 24.2. HRMS (EI) calcd for
C8H11N3O2: [M]þ 181.0851; found, 181.0855.
5.2.1. 2,6-Dichloro-9-(tetrahydrofuran-2-yl)-9H-purine
(3aa).5
8.23 (s,
Yellow powder, 74% yield. 1H NMR (400 MHz, CDCl3, TMS)
d
5.2.9. 9-(1-Butoxybutyl)-2,6-dichloro-9H-purine (3ab).5 Paleyellow
1H), 6.32 (t, J¼4.2 Hz, 1H), 4.21 (dd, J¼14.4, 7.8 Hz, 1H), 4.10 (dd,
powder, 52% yield.1H NMR (400 MHz, CDCl3, TMS)
d 8.29 (s,1H), 5.79
J¼16.0, 7.6 Hz, 1H), 2.56 (m, 2H), 2.17 (m, 2H); 13C NMR (100 MHz,
(dd, J¼7.2, 6.0 Hz, 1H), 3.49 (m, 1H), 3.30 (m, 1H), 2.13 (m, 1H), 1.92
CDCl3)
d 152.7, 152.1, 151.6, 144.1, 131.4, 86.7, 70.1, 32.7, 24.2. HRMS
(m, 1H), 1.47e1.57 (m, 4H), 1.29e1.38 (m, 4H), 0.97 (t, J¼7.6 Hz, 3H),
(EI) calcd for C9H8Cl2N4O: [M]þ 258.0075; found, 258.0079.
0.88 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 153.1,153.1,151.8,
143.6,130.7, 85.6, 69.7, 38.4, 31.2,19.1,18.1,13.7,13.5. HRMS (EI) calcd
5.2.2. 6-Chloro-9-(tetrahydrofuran-2-yl)-9H-purine (3ba).5 Yellow
for C13H18Cl2N4O: [M]þ 316.0858; found, 316.0856.
powder, 65% yield. 1H NMR (400 MHz, CDCl3, TMS)
d 8.75 (s, 1H),
8.24 (s,1H), 6.36 (dd, J¼5.6, 2.6 Hz,1H), 4.32 (dd, J¼10.8, 6.6 Hz,1H),
5.2.10. 2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine
4.11 (dd, J¼10.8, 7.8 Hz, 1H), 2.59 (m, 2H), 2.18 (m, 2H); 13C NMR
(3ac).5 Pale yellow powder, 58% yield. 1H NMR (400 MHz, CDCl3,
(100 MHz, CDCl3)
d
151.8, 151.0, 150.9, 143.4, 132.4, 86.6, 69.9, 32.5,
TMS)
(m, 1H), 2.18 (m, 1H), 2.09 (m, 1H), 1.98 (m, 1H), 1.72e1.86 (m, 2H),
1.67e1.70 (m, 1H); 13C NMR (100 MHz, CDCl3)
152.9, 152.2, 151.7,
d
8.34 (s, 1H), 5.77 (dd, J¼10.8, 2.4 Hz, 1H), 4.19 (m, 1H), 3.78
24.2. HRMS (ESI) calcd for C9H9ClN4O: [MþH]þ 225.0538; found,
225.0546.
d
143.7, 130.8, 82.5, 68.9, 32.0, 24.7, 22.5. HRMS (EI) calcd for
5.2.3. 6-(Di(tert-butyloxycarbonyl)amino)-9-(tetrahydrofuran-2-yl)-
C10H10Cl2N4O: [M]þ 272.0232; found, 272.0236.
9H-purine (3ca).5 Yellow powder, 51% yield. 1H NMR (400 MHz,
DMSO-d6)
d
8.85 (s, 1H), 8.75 (s, 1H), 6.41 (dd, J¼6.4, 3.6 Hz, 1H),
5.2.11. 2,6-Dichloro-9-(1,4-dioxan-2-yl)-9H-purine
(3ad). Yellow
4.16 (dd, J¼14.8, 7.6 Hz, 1H), 3.94 (dd, J¼14.4, 7.0 Hz, 1H), 2.44e2.55
powder, 51% yield. Mp 150e152 ꢀC. 1H NMR (400 MHz, CDCl3, TMS)
(m, 2H), 2.23 (m, 1H), 2.06 (m,1H), 1.38 (s,18H); 13C NMR (100 MHz,
d
8.55 (s, 1H), 6.02 (dd, J¼5.6, 2.8 Hz, 1H), 4.21 (dd, J¼12.4, 3.2 Hz,
CDCl3)
d
152.5, 151.9, 150.5, 150.2, 142.9, 129.5, 86.2, 83.7, 69.8, 32.4,
1H), 4.05 (dd, J¼11.2, 5.2 Hz, 1H), 3.87e3.96 (m, 4H); 13C NMR
27.8, 24.3. HRMS (ESI) calcd for C19H27N5O5: [MþH]þ 406.2085;
(100 MHz, CDCl3) d 153.4, 152.8, 152.1, 144.4, 130.6, 77.7, 68.3, 66.3,
found, 406.2094.
64.2. HRMS (ESI) calcd for C9H8Cl2N4O2: [MþH]þ 275.0097; found,
275.0101.
5.2.4. 4-(Di(tert-butyloxycarbonyl)amino)-6-chloro-9-(tetrahydrofu-
ran-2-yl)-9H-purine (3da). White powder, 55% yield. Mp
5.2.12. 2,6-Dichloro-9-(isochroman-1-yl)-9H-purine (3ae). Yellow
powder, 76% yield. Mp 180e182 ꢀC. 1H NMR (400 MHz, CDCl3, TMS)
215e217 ꢀC. 1H NMR (400 MHz, CDCl3, TMS)
d 8.24 (s, 1H), 6.30 (dd,
J¼6.0, 2.4 Hz, 1H), 4.29 (dd, J¼14.4, 6.4 Hz, 1H), 4.08 (dd, J¼13.0,
d
7.83 (s, 1H), 7.40 (t, J¼6.8 Hz, 1H), 7.32 (d, J¼7.6 Hz, 1H), 7.27 (t,
7.4 Hz, 1H), 2.47e2.60 (m, 2H), 2.12e2.19 (m, 2H), 1.45 (s, 18H); 13C
J¼7.6 Hz, 1H), 7.22 (s, 1H), 6.97 (d, J¼8.0 Hz, 1H), 4.10 (m, 1H), 3.94
NMR (100 MHz, CDCl3) d 151.7, 151.6, 151.0, 150.6, 144.4, 130.7, 86.8,
(m, 1H), 3.12 (m, 1H), 2.98 (dt, J¼16.8, 4.0 Hz, 1H); 13C NMR

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d 153.5, 153.5, 152.0, 144.8, 135.1, 130.9, 129.7,
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129.5, 129.3, 127.4, 126.5, 79.2, 61.3, 27.6. HRMS (EI) calcd for
C14H10Cl2N4O: [M]þ 320.0232; Found, 320.0234.
5.2.13. 2,6-Dichloro-9-(tetrahydro-5-methylfuran-2-yl)-9H-purine
(3af). Yellow oil, 70% yield. 1H NMR (400 MHz, DMSO-d6)
d 8.85 (s,
2. (a) Hilbert, G. E.; Johnson, T. B. J. Am. Chem. Soc. 1930, 52, 4489; (b)
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1H), 8.80 (s, 1H), 6.36 (dd, J¼6.8, 4.4 Hz, 1H), 6.25 (dd, J¼6.8, 3.2 Hz,
1H), 4.52 (m,1H), 4.20 (m,1H), 2.44e2.62 (m, 4H), 2.30 (m,1H), 2.14
(m, 1H), 1.87 (m, 1H), 1.65 (m, 1H), 1.31 (d, J¼6.0 Hz, 3H), 1.22 (d,
J¼6.0 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d 153.2, 153.0, 152.3,
€
3. (a) Niedballa, U.; Vorbruggen, H. J. Org. Chem. 1976, 41, 2084; (b) Masami, O.;
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5.3. Representative procedure of the N-alkoxyalkylation re-
action using DMSO as solvent
Into an oven-dried flask, 2,6-dichloropurine 1a (1.0 mmol),
diethoxymethane 2h (4 mmol), CuCl2 (0.1 mmol), ligand
(0.1 mmol), and TBHP (5e6 M in decane, 5.0 mmol) were added in
DMSO (2 mL) at room temperature. The mixture was allowed to
react at 70 ꢀC for 48 h. After the completion of the reaction, the
mixture was filtered through a pad of Celite. The filtrate was par-
titioned by EtOAc (10 mL) and brine (10 mL). After separation of the
aqueous layer, the organic layer was washed twice by brine (10 mL).
Then the organic layer was dried with Na2SO4, and further con-
centrated until the solvent was completely removed. The residue
was finally separated on a silica gel column and afforded the final
product.
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5.3.1. 2,6-Dichloro-9-(ethoxymethyl)-9H-purine (3ag). White pow-
der, 55% yield. Mp 125e127 ꢀC. 1H NMR (400 MHz, CDCl3, TMS)
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12. One of the reviewers suggested that this reaction was an oxonium process and
advised us optimize the common Lewis acids for the reaction. However, we
conducted this reaction under various Lewis acid conditions, such as SnCl4,
TMSOTf, BF3$Et2O, FeCl3 and ZnI2, finding no products was provided with the
nucleobases were destroyed or fully recovered. A possible reason for these
results was that the unsilylated purine could form complexes with Lewis acids,
and thereof hampered the reaction. Detailed results could be found in SD (Table
S1).
d
8.27 (s, 1H), 5.64 (s, 2H), 3.59 (q, J¼7.2 Hz, 2H), 1.20 (t, J¼6.8 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 153.5, 153.4, 152.0, 145.8, 130.6,
73.3, 66.0, 14.8. HRMS (ESI) calcd for C8H8Cl2N4O: [MþH]þ
247.0148; found, 247.0159.
Acknowledgements
The authors gratefully thank the grant support from Zhejiang
Provincial Natural Science Foundation of China (Y4090408) and the
Hangzhou City Research Project (20090331N04).
€
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Supplementary data
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Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.11.020.
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